Primary vulval melanoma and genital lichen sclerosus

Abstract Background Lichen sclerosus (LS) is a chronic, inflammatory skin disease with a predilection for the genitalia. Although, the association between squamous cell cancer and genital LS is well established, a link with genital melanoma has not been thoroughly explored. However, we have recently published a case series of penile melanoma where 9/11 (82%) of patients seen over a 10 year period with penile melanoma were retrospectively found to have histological and/or clinical evidence of genital LS on review. Objectives The aim of this study was to illuminate further the relationship between vulval melanoma and genital LS by reviewing all the cases managed by our hospital and undertaking a literature review. Methods We identified all the cases with a diagnosis of vulval melanoma over a 16‐year period (2006–2022) where histology was available. The clinical notes were retrospectively reviewed, and the histological features of all cases were reassessed by two independent mutually ‘blinded’ histopathologists. We also performed a literature review of genital LS in patients with vulval melanoma. Results A total of 11 patients with vulval melanoma were identified for the review. Histopathological review found evidence of genital LS in seven of them (64%). Genital LS was not documented in any of the original histology reports. Clinical notes and letters were available in nine cases. The literature review identified 12 relevant studies with a total of 18 patients. Twelve cases concerned adult women, and six concerned female children. Conclusion The presence of genital LS in as high as 64% of our vulval melanoma cases might indicate a causative relationship between genital LS and vulval melanoma. The pathogenesis of vulval melanoma remains largely unknown. Although ultraviolet radiation is an important pathogenic factor for cutaneous melanoma, it cannot be a factor in vulval melanoma. While possible mechanisms behind this association remain unclear, it is possible that chronic inflammation from genital LS leads to melanocytic distress and increased mutagenesis.


| METHODS
The aim of this study was to explore further the relationship between vulval melanoma and genital LS.
We retrospectively identified all cases of vulval melanoma managed in our department over a 16-year period for which histopathological material was available (2006-2022).The histological features of all cases were reviewed by two independent, mutually 'blinded' histopathologists.In cases of diagnostic discordance between the two histopathologists, the slides were further reviewed by a third independent histopathologist.
Additionally, we performed a literature search on articles and included those that mentioned cases with both vulval melanoma and vulval LS.

| RESULTS
A total of 11 patients were identified.The median age at diagnosis of vulval melanoma was 64 years (range 48-87 years) and the majority of patients (73%) were White British.The most common subtype of melanoma seen was superficial spreading (seven cases, 64%), with nodular melanoma recorded in three cases (27%,) and mucosal melanoma in one case (9%).Cancer staging was found to be as follows: pTis in three cases (30%), pT2a in two cases (20%), pT2b (10%) in one case, pT3a in one case (10%), pT4a in one case (10%) and PT4b in two cases (20%).Staging was not available in one case.KIT mutation was only identified in one case.
Significantly, LS was not mentioned in the clinical records of any patient, no clinical photographs were available for review, and LS was not mentioned in any of the original histology reports.
Overall, genital LS was histologically present in seven cases (64%) and absent in four (36%) (see Figures 1 and 2).Histopathological findings for genital LS were concordantly positive in one case and concordantly negative in four cases.In the six cases in which histopathological opinions were discordant, a third histopathologist reviewed the cases and deemed genital LS to be present in all six.

| DISCUSSION
0][11][12][23][24][25][26][27][28][29] Similarly, penile melanoma is a rare entity that accounts for less than 1.4% of all primary penile cancers, and less than 0.1% of all melanomas in the male sex and mainly affects older men. 30at is already known?� Vulval melanoma is an uncommon condition with a poor prognosis that accounts for up to 10% of all primary vulval malignancies and for 1%-2% of all melanomas in females.� Although, the association between squamous cell cancer (SCC) and genital lichen sclerosus (LS) is well established, a link between LS and genital melanoma has not been thoroughly explored.

What does this study add?
� This study highlights that the presence of genital LS in as high as 64% of our vulval melanoma cases might indicate a causative relationship between genital LS and vulval melanoma.� While the mechanisms behind the association of genital LS and vulval melanoma remain unclear, our findings have implications for the early diagnosis, management and follow-up of genital LS.
Several pathogenic factors have been studied for their role in vulval melanoma, including viruses [e.g.][33][34][35] Vulval melanoma usually affects the glabrous (nonhair-bearing) parts of the vulva, most commonly the labia minora, the labia majora and clitoris. 4,16,19,24,36,37lval LS is a chronic progressive inflammatory skin disorder that primarily involves the glabrous skin. 1,38lthough a number of aetiological mechanisms have been proposed (including genetic, hormonal, irritant, traumatic and infectious factors), the exact aetiopathogenesis remains controversial. 38t is now well recognized that women with vulval LS have an increased risk for developing vulval SCC. 1,38,39he estimated lifetime risk of vulval SCC in patients with genital LS ranges from 2.2% to 5%. 1,39,40However, this has not been quantified in untreated patients or in relation to the length of time that the disease has been present. 41It is believed that early detection and treatment can lead to reduction in the risk of developing SCC. 39,41][6][7][8][9][10][11][12][13][14][15][16][17][18] To our knowledge, there have been 18 previously published cases of vulval melanomas coexisting with genital LS and 12 cases of penile melanomas linked to genital LS. [5][6][7][8][9][10][11][12][13][14][15][16][17][18] Also, it should be noted that there are no case reports of vulval melanomas in juveniles without LS. 42,43 study in 2018 based on data extracted from the Finnish Cancer Registry found 249 patients with biopsy-confirmed vulval LS, of whom three also had vulval melanomas. 14From the same registry, 30 cases of SCC were found among patients with vulval LS.Conversely, six cases of melanomas were identified among patients who did not have genital LS from a total of 250 000 females.The overall risk of vulval melanoma for patients with vulval LS was thus estimated to be 341 times higher than the risk for patients without vulval LS (p < 0.001). 14ur findings are in line with these publications.Recent work by our group reported evidence of LS in 82% of all penile melanomas. 5The rates of genital LS found in this study in females are lower (64%), but they still support an association.Comparing the prevalence of vulval LS in the general population (0.1%-1.7%) with the prevalence of vulval LS in vulval melanoma demonstrated in this review (64%) gives perspective to the strength of the correlation. 44e thus argue that the actual prevalence of genital LS in vulval melanoma is higher than that which is reflected in the existing literature.
It seems likely that the striking histological features of vulval melanoma overshadow the more subtle features of genital LS, so that genital LS is underrecognized and under-reported, analogous to the situation observed in genital skin adjacent to SCC, and thus only detected when determinedly sought out, as in this case series. 5,12,45,46n addition, the observation that the histological features of LS appear to disappear under melanoma, but not under naevi, might contribute to the difficulty in the diagnosis of LS in this context. 5,12enital skin is largely unexposed through life to UV radiation-the predominant environmental melanocytic carcinogen.UV cannot therefore be credibly considered a causative factor in vulval melanoma.It seems more plausible, instead, that in genital skin local stressors and defective mechanisms of local tissue homoeostasis are responsible for the development of melanoma. 47 is possible that molecular events involved in squamous carcinogenesis in genital LS to SCC are also relevant in the development of melanoma.But they might equally be independent.Some of the pathological mechanisms implicated in genital LS involve immunogenic activation, sclerosis and oxidative stress. 38,39enital LS may be responsible for generating a prooxidative environment that increases the risk of mutations whilst also altering the extra-cellular matrix composition, leading to clonal expansion of damaged melanocytes. 5,129][50] LS could be exhibiting a regenerative phenotype as a response to stromal fibrosis and sclerosis, whist also preventing the function of T-cytotoxic T lymphocytes allowing for the expansion of melanocytes with an abnormal phenotype. 12][53] Soufir et al. demonstrated that inactivating mutations of the p53 and CDKN2A genes were present in 100% of LS-derived genital tumours.Although, they seemed to occur later in oncogenesis as they were not present in the initial LS lesions.In addition, an overexpression of the p53 wild-type protein has been observed in LS, reflecting stress response to inflammation and carcinogenic insults. 52everal studies suggest that C-KIT, TP53 and NRAS mutations are seen with high frequency in vulval melanoma.BRAF mutations in vulval melanomas seems to be less frequent, compared to cutaneous melanomas, probably due to the absence of UV mutational signature in vulval melanomas. 22,54,55elanocytic dysfunction and distress are commonly seen during and after genital LS, manifesting as benign vulval melanosis, and there is a literature attesting to the challenges this can create in the differential diagnosis of these lesions. 2,12,49,56For this reason, we need to be careful when considering vulval melanoma in a background of LS, especially in children and adolescents. 42,49Melanocytic hyperplasia has been documented in LS, but it is generally rare and difficult to interpret.Benign melanocytic naevi can be encountered in genital LS that sometimes histologically resemble melanoma. 6,12,49,56,57It is not clear whether melanocytic lesions (such as naevi or vulval melanosis) were present in any of our cases prior to the development of the malignant lesion.However, it is possible that LS could also induce the formation of a melanocytic nevus from either/or predisposed melanocytes, an activated mesenchyme and pathologically changed extracellular matrix of LS. 12 This study is limited by its size and the retrospective collection of data, and the lack of clinical photographs.It can be argued that the histopathology findings may have been distorted by subjectivity.We attempted to mitigate this possibility by engaging two histopathologists to review the histology independently, with a third histopathologist recruited to address any discordant findings.

| CONCLUSION
The histological presence of genital LS in seven out of 11 patients with vulval melanoma raises the hypothesis of a causative relationship between the two conditions.We postulate that the limited number of reports on this topic are related to clinical and histological underrecognition and under-reporting of genital LS.It is suggested that chronic inflammation from genital LS leads to melanocytic distress and increased mutagenesis.This notion is further supported by the absence of UV mutational signatures in vulval melanomas and the anatomical and multi-focal presentation of vulval melanomas, which mirrors that of genital LS.While the mechanisms behind this association remain unclear, our findings have implications for the early diagnosis, management and follow-up of genital LS.

F I G U R E 1
Vulval excision for melanoma (haematoxylin and eosin, original magnification x2).(a) Infiltrating nodules of invasive melanoma extending into the dermis; (b) the adjacent surface epithelium shows epidermal atrophy, loss of skin adnexal structures, fibrosis in the superficial dermis and a lichenoid band of chronic inflammation in keeping with lichen sclerosus.F I G U R E 2 Vulval excision for melanoma.(a) Superficially spreading melanoma containing multiple clusters of atypical melanocytes in the epidermis (haematoxylin and eosin, original magnification x40); (b) a section from the background skin from the same patient showing features in keeping with lichen sclerosus (epidermal atrophy, loss of rete ridges, lichenoid band of inflammation and subepithelial sclerosis) (haematoxylin and eosin, original magnification x10).